Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2

Abstract

Phosphoenolpyruvate carboxykinase 1 (PEPCK1) is the critical enzyme for gluconeogenesis and is linked with type II diabetes. Previous studies have found that SIRT2, a deacetylase, plays an important role in deacetylating PEPCK1 and little is known about the anti-diabetic activity of SIRT2 inhibitors. In this study, we investigated the anti-diabetic effects of sirtinol, a SIRT2 inhibitor, on cell gluconeogenesis in vivo and in vitro. Immunoblotting analysis revealed that sirtinol significantly decreased the protein level of PEPCK1, and was accompanied by the hyperacetylation of PEPCK1 as well as decreased glucose output in a dose-dependent manner. Furthermore, sirtinol exerted little impact on endogenous PEPCK1 levels in SIRT2-knockdown cells. The in vitro experiments further confirmed the in vivo data; sirtinol decreased liver PEPCK1 protein level and prevented pyruvate-induced blood glucose from increasing. Based on our results, the rate-limiting enzyme PEPCK1 is the primary target of sirtinol, and the inhibition of SIRT2 activity may play an important role in cell gluconeogenesis. Thus, SIRT2 may be a novel molecular target for diabetes therapy and may thus shed light on the underlying diabetes treatment mechanisms of sirtinol.

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

“…This was revealed at the level of oscillatory activity characteristics, pointing to an overall slowing of brain rhythms with particular abnormalities in the delta (<4Hz) and beta (~20Hz) frequency ranges [397–402]. Moreover, alteration of resting state networks, correlated with memory impairment, was recently shown using a graph-theoretical approach applied to neuromagnetic data [403]. Important questions are: When do these changes emerge in the course of the disease and which changes are predictive of or specific for the development of molecular and clinical AD?…”

Biological Effects and Properties of Eukaryotic Sirtuins

“…Так, розроблено такі аналоги ресвератролу, як SRT1720, SRT1460, SRT2183 і SRT2104. Вони, за твердженнями деяких дослідників, здатні підвищити середню тривалість життя і захистити від певних вікових захворювань [1,17,52,[57][58][59].…”

Cyclotron production and radiochemical separation of 55Co and 58mCo from 54Fe, 58Ni and 57Fe targets

“…Cobalt-55 ( t 1/2 = 17.53 h, 76% β + , E max = 1498 keV) is an intermediate-lived positron-emitting radionuclide that is a useful radiotracer for positron emission tomography (PET) (De Reuck et al, 2004, 1999; Jansen et al, 1997a, 1997b, 1994, 1996b, 1995; Korf et al, 1998; Stevens et al, 1999) and particularly useful for labeling proteins due to its favorable complexation with established bifunctional chelators (Dam et al, 2016; Garousi et al, 2017; Mastren et al, 2015; Srivastava et al, 1994; Thisgaard et al, 2011b; Wallberg et al, 2010). Furthermore, when chelated in oxidation state 3+, the formed complex is considered inert (Duckworth et al, 2009; Regoeczi et al, 1995; Wegner and Spatz, 2013) and therefore it is less prone to interact with ligands in blood plasma and non-targeted organs due to trans-chelation.…”

“…So far, only seven studies have followed this chelator-based approach (Dam et al, 2016; Garousi et al, 2017; Goethals et al, 2000; Mastren et al, 2015; Srivastava et al, 1994; Thisgaard et al, 2011b; Wallberg et al, 2010). Goethals et al (Goethals et al, 2000) labeled 55 Co to ethylene diamine tetraacetic acid (EDTA) and characterized this complex for the application in the measurement of the glomerular filtration rate in kidneys via PET, a study which is commonly performed with the perfusion tracer 51 Cr-EDTA (Chantler et al, 1969).…”